Hypertension is the 2nd major etiology of chronic kidney disease (CKD), a progressive disorder affecting almost 14% of the general population. Patients with CKD in turn associates to hypertension (< 95%) and have higher rates of hospitalization, healthcare costs, cardiovascular mortality, and shorter life expectancy than non-CKD patients. Chronic renovascular disease (RVD) is the main cause of renovascular hypertension that develops in up to 11% of the US adults and increases risk of CKD by 25%. Despite the availability of treatments for RVD, renal function and hypertension do not improve or even deteriorates in over half of the patients, showing that treatments are still ineffective and highlighting the need of new treatments and strategies for these patients with higher mortality and risk of CKD. Our seminal work during the previous funding cycle of HL095638 showed that a progressive damage and loss of the renal microcirculation is a pivotal mechanism for renal injury and hypertension in RVD. We also showed that intra-renal single-dose therapy using recombinant human vascular endothelial growth factor (rh-VEGF) largely preserved the renal microcirculation and improved renal function in a swine model of RVD and hypertension. These effects were significant but still insufficient to fully reverse injury or hypertension despite VEGF being administered at an early stage of RVD. A potential reason for the incomplete resolution of renal damage is the short half-life of VEGF. Recently, we have developed a bioengineered protein polymer fused to rh-VEGF that greatly stabilizes VEGF from degradation and clearance. We showed that this protein-based polymer, called Elastin-like Polypeptide (ELP), naturally accumulates at high levels in the kidney. Our compelling preliminary data show that single intra-renal administration of an ELP- VEGF fusion improved renal function, microvascular injury, and hypertension in the swine RVD model more efficiently that free VEGF therapy. In addition, we developed engineered versions of the polymer, containing kidney targeting peptides (KTP) that further increase kidney deposition and specificity (KTP-ELP). Thus, the proposed studies in the renewal of HL095638 will extend the previous contributions by developing a new treatment with high potential for clinical translation. We recently developed and characterized a KTP-ELP- VEGF construct. This proposal will first assess the effectiveness of KTP-ELP to improve renal deposition and reduce off-target binding of VEGF. We will determine the specific intra-renal localization and cell-type binding in vitro and in vivo. We will use genetically modified mice models and a translational swine model of RVD and hypertension to collect pharmacokinetic, biodistribution, safety, and efficacy data needed to propel the advance of this technology towards clinical testing. Second, we will determine the therapeutic efficacy and mechanisms of renoprotection of minimally invasive single-dose intra-renal administration of KTP-ELP-VEGF to improve hypertension, renal function and microvascular injury. Finally, we will determine the efficacy and mechanisms of KTP-ELP-VEGF therapy after systemic, non-invasive, single-dose (repeated if needed) administration.